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  1. Article: Correction: Gallus et al. Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma.

    Gallus, Marco / Kwok, Darwin / Lakshmanachetty, Senthilnath / Yamamichi, Akane / Okada, Hideho

    Cancers

    2023  Volume 16, Issue 1

    Abstract: It has come to our attention that the previously published manuscript contained an outdated iteration of Table 1 [ ... ]. ...

    Abstract It has come to our attention that the previously published manuscript contained an outdated iteration of Table 1 [...].
    Language English
    Publishing date 2023-12-26
    Publishing country Switzerland
    Document type Published Erratum
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers16010119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma.

    Gallus, Marco / Kwok, Darwin / Lakshmanachetty, Senthilnath / Yamamichi, Akane / Okada, Hideho

    Cancers

    2023  Volume 15, Issue 14

    Abstract: Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular ... ...

    Abstract Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase (IDH) enzymes, resulting in an altered cellular energy metabolism and the production of the oncometabolite D-2-hydroxyglutarate. Despite the remarkable progress in improving the extent of resection and adjuvant radiotherapy and chemotherapy, LGG remains incurable, and secondary malignant transformation is often observed. Therefore, novel therapeutic approaches are urgently needed. In recent years, immunotherapeutic strategies have led to tremendous success in various cancer types, but the effect of immunotherapy against glioma has been limited due to several challenges, such as tumor heterogeneity and the immunologically "cold" tumor microenvironment. Nevertheless, recent preclinical and clinical findings from immunotherapy trials are encouraging and offer a glimmer of hope for treating IDH-mutant LGG patients. Here, we aim to review the lessons learned from trials involving vaccines, T-cell therapies, and IDH-mutant inhibitors and discuss future approaches to enhance the efficacy of immunotherapies in IDH-mutant LGG.
    Language English
    Publishing date 2023-07-22
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers15143726
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: T-Cell based therapies for overcoming neuroanatomical and immunosuppressive challenges within the glioma microenvironment.

    Kwok, Darwin / Okada, Hideho

    Journal of neuro-oncology

    2020  Volume 147, Issue 2, Page(s) 281–295

    Abstract: Glioblastoma remains as the most common and aggressive primary adult brain tumor to date. Within the last decade, cancer immunotherapy surfaced as a broadly successful therapeutic approach for a variety of cancers. However, due to the neuroanatomical and ...

    Abstract Glioblastoma remains as the most common and aggressive primary adult brain tumor to date. Within the last decade, cancer immunotherapy surfaced as a broadly successful therapeutic approach for a variety of cancers. However, due to the neuroanatomical and immunosuppressive nature of malignant gliomas, conventional chemotherapy and radiotherapy treatments garner limited efficacy in patients with these tumors. The intricate structure of the blood brain barrier restricts immune accessibility into the tumor microenvironment, and malignant gliomas can activate various adaptive responses to subvert anticancer immune responses and reinstate an immunosuppressive milieu. Yet, evidence of lymphocyte infiltration within the brain and recent advancements made in cell engineering technologies implicate the vast potential in the future of neuro-oncological immunotherapy. Previous immunotherapy platforms have paved way to improved modalities, which includes but is not limited to personalized vaccines and chimeric antigen receptor T-cell therapy. This review will cover the various neuroanatomical and immunosuppressive features of central nervous system tumors and highlight the innovations made in T-cell based therapies to overcome the challenges presented by the glioblastoma microenvironment.
    MeSH term(s) Animals ; Brain Neoplasms/immunology ; Brain Neoplasms/pathology ; Brain Neoplasms/therapy ; Glioma/immunology ; Glioma/pathology ; Glioma/therapy ; Humans ; Immunosuppression Therapy ; Immunotherapy, Adoptive/methods ; T-Lymphocytes/immunology ; T-Lymphocytes/transplantation ; Tumor Microenvironment/immunology
    Language English
    Publishing date 2020-03-17
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 604875-4
    ISSN 1573-7373 ; 0167-594X
    ISSN (online) 1573-7373
    ISSN 0167-594X
    DOI 10.1007/s11060-020-03450-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1825: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

    Nejo, Takahide / Wang, Lin / Leung, Kevin K / Wang, Albert / Lakshmanachetty, Senthilnath / Gallus, Marco / Kwok, Darwin W / Hong, Chibo / Chen, Lee H / Carrera, Diego A / Zhang, Michael Y / Stevers, Nicholas O / Maldonado, Gabriella C / Yamamichi, Akane / Watchmaker, Payal B / Naik, Akul / Shai, Anny / Phillips, Joanna J / Chang, Susan M /
    Wiita, Arun P / Wells, James A / Costello, Joseph F / Diaz, Aaron A / Okada, Hideho

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 6362

    Abstract: Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative ... ...

    Abstract Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
    MeSH term(s) Humans ; Alternative Splicing ; Antigens, Surface ; Glioma/genetics ; Glioblastoma ; Histocompatibility Antigens ; RNA ; Antigens, Neoplasm/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 5
    Chemical Substances Antigens, Surface ; Histocompatibility Antigens ; RNA (63231-63-0) ; Antigens, Neoplasm ; PTPRZ1 protein, human (EC 3.1.3.48) ; Receptor-Like Protein Tyrosine Phosphatases, Class 5 (EC 3.1.3.48)
    Language English
    Publishing date 2024-03-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-56684-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens.

    Damo, Martina / Hornick, Noah I / Venkat, Aarthi / William, Ivana / Clulo, Kathryn / Venkatesan, Srividhya / He, Jiaming / Fagerberg, Eric / Loza, Jennifer L / Kwok, Darwin / Tal, Aya / Buck, Jessica / Cui, Can / Singh, Jaiveer / Damsky, William E / Leventhal, Jonathan S / Krishnaswamy, Smita / Joshi, Nikhil S

    Nature

    2023  Volume 619, Issue 7968, Page(s) 151–159

    Abstract: The peripheral T cell repertoire of healthy individuals contains self-reactive T ... ...

    Abstract The peripheral T cell repertoire of healthy individuals contains self-reactive T cells
    MeSH term(s) Animals ; Humans ; Mice ; Antigens/immunology ; Biopsy ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/pathology ; Epidermis/immunology ; Epidermis/metabolism ; Gene Expression Profiling ; Immune Tolerance ; Lichen Planus/immunology ; Lichen Planus/pathology ; Programmed Cell Death 1 Receptor/immunology ; Programmed Cell Death 1 Receptor/metabolism ; Skin/cytology ; Skin/immunology ; Skin/metabolism ; Skin/pathology
    Chemical Substances Antigens ; PDCD1 protein, human ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2023-06-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06217-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

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  6. Article: Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

    Nejo, Takahide / Wang, Lin / Leung, Kevin K / Wang, Albert / Lakshmanachetty, Senthilnath / Gallus, Marco / Kwok, Darwin W / Hong, Chibo / Chen, Lee H / Carrera, Diego A / Zhang, Michael Y / Stevers, Nicholas O / Maldonado, Gabriella C / Yamamichi, Akane / Watchmaker, Payal / Naik, Akul / Shai, Anny / Phillips, Joanna J / Chang, Susan M /
    Wiita, Arun P / Wells, James A / Costello, Joseph F / Diaz, Aaron A / Okada, Hideho

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Background: Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider ... ...

    Abstract Background: Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of neoantigens.
    Results: In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface neoantigens that could be targeted by antibodies and chimeric antigen receptor (CAR)-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas [TCGA]) and 9,166 normal tissue samples (from the Genotype-Tissue Expression project [GTEx]), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including
    Conclusions: Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
    Language English
    Publishing date 2023-11-02
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.26.564156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

    Mathur, Radhika / Wang, Qixuan / Schupp, Patrick G / Nikolic, Ana / Hilz, Stephanie / Hong, Chibo / Grishanina, Nadia R / Kwok, Darwin / Stevers, Nicholas O / Jin, Qiushi / Youngblood, Mark W / Stasiak, Lena Ann / Hou, Ye / Wang, Juan / Yamaguchi, Takafumi N / Lafontaine, Marisa / Shai, Anny / Smirnov, Ivan V / Solomon, David A /
    Chang, Susan M / Hervey-Jumper, Shawn L / Berger, Mitchel S / Lupo, Janine M / Okada, Hideho / Phillips, Joanna J / Boutros, Paul C / Gallo, Marco / Oldham, Michael C / Yue, Feng / Costello, Joseph F

    Cell

    2024  Volume 187, Issue 2, Page(s) 446–463.e16

    Abstract: Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial ...

    Abstract Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.
    MeSH term(s) Humans ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Epigenomics ; Genomics ; Glioblastoma/genetics ; Glioblastoma/pathology ; Single-Cell Analysis ; Tumor Microenvironment ; Models, Biological ; Genetic Heterogeneity
    Language English
    Publishing date 2024-01-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2023.12.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1167: Show issues Location:
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    Zs.MG 58: Show issues

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  8. Article: Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens.

    Kwok, Darwin W / Stevers, Nicholas O / Nejo, Takahide / Chen, Lee H / Etxeberria, Inaki / Jung, Jangham / Okada, Kaori / Cove, Maggie Colton / Lakshmanachetty, Senthilnath / Gallus, Marco / Barpanda, Abhilash / Hong, Chibo / Chan, Gary K L / Wu, Samuel H / Ramos, Emilio / Yamamichi, Akane / Liu, Jerry / Watchmaker, Payal / Ogino, Hirokazu /
    Saijo, Atsuro / Du, Aidan / Grishanina, Nadia / Woo, James / Diaz, Aaron / Chang, Susan M / Phillips, Joanna J / Wiita, Arun P / Klebanoff, Christopher A / Costello, Joseph F / Okada, Hideho

    bioRxiv : the preprint server for biology

    2023  

    Abstract: T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public ... ...

    Abstract T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide. We identified CD8+ T-cell clones specific for neoantigens derived from tumor-wide and conserved neojunctions in
    Language English
    Publishing date 2023-10-20
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.19.563178
    Database MEDical Literature Analysis and Retrieval System OnLINE

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